"You may not be able to finish the work, but you are commanded never to abandon it,"

Rabbi Tarfon, Pirkei Avot 2:21

While not found within biblical texts themselves, later rabbinic works evoke a sentiment appropriate and timely today in a complex and challenging landscape begging for answers to more than matters of reproductive choice. This month we tackle the ever-growing challenges faced by practitioners and patients seeking outcomes at the very core of family building, knowing well that it all starts with gametes. The journey referred to as gametogenesis is a highly engineered product of evolution aimed at yielding gametes, which if interacting at the right time and place, set the stage for fertilization and the prospect that viable offspring will result [1]. But as ARTs and MARs have evolved into sophisticated and clever manipulations of human reproductive biology, so too have the frailties of human nature commanded a closer introspective look at just how little we know and understand about our own fecundity as a species prone to reproductive failure. Indeed, we seek to encourage the work involved in gametogenesis (and meddle with it) and feel obliged to never give up. So it seems.

Building a developmentally competent gamete, that is one that upon fertilization will overlook and guide the later critical steps of development, is hardly limited to the wonders of sperm and oocyte differentiation taking place within the cozy confines of seminiferous tubules or ovarian follicles. What Chang came to understand about capacitation in the male reproductive tract has now gained a sense of perspective for the female gamete and all that transpires within gonadal and extragonadal niches [2, 3], and the environmental influences imposed on niche functions in dynamic and stressful states, whether as a result of natural or iatrogenic exposures implicit to ART and MAR manipulations.

Among the more recent environmental influencers assuming centerish stage is that of the microbiome. This month, Cannarella and colleagues draw our attention to the possible impact of seminal fluid microbiota on testicular steroidogenesis, one of the singularly physiological factors regulating sperm quality and male reproductive fitness (The influence of seminal microbiota on human testicular steroidogenesis: a prospective study; https://doi.org/10.1007/s10815-024-03351). The advancing domain of oocyte in vitro maturation (IVM) is gaining momentum both as a clinical imperative and directive for managing lifestyle effects within the purview of contemporary ARTs. Controlling the poorly understood capabilities endowed in a mature oocyte poised to confront and surmount the challenges imposed after ICSI or IVF, is but one dimension of IVM that this issue addresses the gametogenesis workflow from lifestyle to mitochondrial genomes (New aspect on the regulation of in vitro oocyte maturation: role of the obesity, neuropeptides and adipokines; https://doi.org/10.1007/s10815-024-03345).

From Kofinas and collaborators comes an intriguing set of findings on oocytes retrieved in an immature state after controlled ovarian stimulation and analyzed, after rescue IVM (rIVM), for the presence of deletions in mitochondrial DNA (mtDNA) (Oocytes with impaired meiotic maturation contain increased mtDNA deletions; https://doi.org/10.1007/s10815-025-03393). That they observe that the load of mutations correlates with the level of immaturity, at the time of collection and after rIVM, implies that during the extended intrafollicular course of development, accumulation of mutations in some way plays into the failure to acquire and express meiotic competence-perhaps due to an intrinsic, and as yet underappreciated, checkpoint to cell cycle progression executed at the level of mtDNA integrity.

The workload embedded within the process of oogenesis culminates during meiotic maturation with the integration and synchronization of cytoplasmic and nuclear events following the protracted periods of oocyte growth and differentiation within the developing follicle, as highlighted by studies on mouse oocytes [4]. But with the increasing availability of human oocytes for research into transcriptomics in the context of IVM, detailed molecular maps are emerging that will likely guide the construction project that is oogenesis to a clinically favorable endpoint [5]. And coupled with insights gleaned from GWAS analyses aimed at uncovering genetic determinants of infertility, candidates based on mutations are emerging at the level of both germline and gonadal tissue gene products that together comprise a workforce aimed at seeing gametogenesis to its fitting and most evolutionarily relevant conclusion-reproduction!

The latest of these studies draws attention to critical transcription factors engaged in sustaining patterns of gene expression from the earliest stages of oogenesis [6]. One such transcription factor that seems to repeatedly rear its head is TBPL2, a gene in which specific mutations have been noted that already have been implicated clinically in patients exhibiting problems with follicular development [7]. Just how early changes in gene expression contribute to the appearance of defects at distinct stages of oogenesis remain an area of active investigation but it is becoming clear that a temporal offset at ends of the oocyte developmental spectrum are coupled in as yet unresolved ways (Oocyte/zygote/embryo maturation arrest: a clinical study expanding the phenotype of NOBOX variants; https://doi.org/10.1007/s10815-025-03402).

While abandoning our commitments to advancing patient care would be the antithesis of our collective goal to couple an existing knowledge base to best clinical practices, we should remain mindful that we are in the midst of a misinformation era in ARTs and MAR not unlike that permeating society at a grander scale. A case in point is made clear by the study of Linderkugel and colleagues who confirm and extend the notion that endometrial scratching fails to improve euploid embryo transfer outcomes and may in fact pose downstream risks during second trimester (Endometrial scratching before euploid embryo transfer: a case–control study; https://doi.org/10.1007/s10815-024-03360). A word to the wise is sufficient as we take our own discretionary matters to heart when the patient, and not the business, is the the most purposeful outcome.